Until the mid-1980s, the accepted treatment for coronary atherosclerosis, i.e., narrowing of the coronary artery(ies) was coronary by-pass surgery. While being quite effective and having evolved to a relatively high degree of safety for such an invasive procedure, by-pass surgery still involves potentially serious complications and generally results in an extended recovery period.
With the advent of percutaneous transluminal coronary angioplasty (PTCA) in 1977, the scene changed dramatically. Using catheter techniques originally developed for heart exploration, inflatable balloons were deployed to re-open occluded regions in arteries. The procedure was relatively non-invasive, took a very short time compared to by-pass surgery and the recovery time was minimal. However, PTCA brought with it other problems such as vasospasm and elastic recoil of the stretched arterial wall which could undo much of what was accomplished and, in addition, engendered a new problem, restenosis, the re-clogging of the treated artery due to neointimal hyperplasia.
The next improvement, advanced in the mid-1980s, was the use of a stent to maintain luminal diameter after being re-established using PTCA. This for all intents and purposes put an end to vasospasm and elastic recoil but did not resolve the issue of restenosis. That is, prior to the introduction of stents, restenosis occurred in from about 30 to 50% of patients undergoing PTCA. Stenting reduced this to about 15 to 20%, a substantial improvement but still more than desirable.
In 2003, the drug-eluting stent (DES) was introduced. The drugs initially used with DESs were cytostatic compounds, that is, compounds that curtailed the proliferation of cells that resulted in restenosis. The occurrence of restenosis was reduced to about 5 to 7%, a relatively acceptable figure. However, the use of DESs engendered yet another complication, late stent thrombosis, the forming of blood clots long after the stent was in place. It was hypothesized that the formation of blood clots was most likely due to delayed healing, a side-effect of the use of cytostatic drugs.
It was found that the physiopathology of restenosis involves early injury to smooth muscle cells (SMCs), de-endothelialization and thrombus deposition. Over time, this leads to SMC proliferation and migration and extra-cellular matrix deposition. There is an increasing body of evidence suggesting that inflammation plays a pivotal role in linking this early vascular injury with neointimal growth and eventual lumen compromise, i.e., restenosis. Further, it has been observed that, when stents are used, the inflammatory state if often more intense and prolonged, exacerbating the situation.
To deal with the above, dual-drug DESs are being developed which comprise an anti-proliferative drug to combat SMC proliferation and an anti-inflammatory drug to reduce inflammation. A particularly noteworthy family of anti-proliferative drugs is the mammalian target of rapamycin (mTOR) inhibitor family. mTOR inhibitors mitigate restenosis through inhibition of smooth muscle cell growth. mTORs are, however, non-specific and also inhibit the growth of endothelial cells, which has been suggested to possibly slow the overall healing process.
Inflammation is, of course, a normal response to injury and is necessary for the healing process. However, chronic inflammation can be detrimental to healing in that the constant recruitment of monocytes, lymphocytes and neutrophils leads to a constant generation of inflammatory cytokines along with reactive oxygen species and enzymes generated by inflammatory cells to remove foreign bodies or damaged tissue. Thus, anti-inflammatory drugs are often included in dual drug DESs to control chronic inflammation by reducing cytokine-driven neotintimal growth. Long-term administration of anti-inflammatory drugs, however, can shut down the healing process completely.
While generally effective, current single- and dual-drug DESs have not completely served certain patient groups. For example, in the SIRIUS clinical trial, patients with diabetes were roughly twice as likely as non-diabetics to incur binary restenosis. Further, diabetic patients tend to be more prone, post vascular repair surgery, to major adverse cardiac events (MACE). It has been observed, however, that increased MACE events such as acute myocardial infarction (AMI), thrombosis and cardiac death in diabetics during approximately the first year post stent placement correlate with target lesion revascularization (TLR) rather than with non-TLR-related causes. TLR, in turn, correlates well with the presence of restenosis in, closely proximal to or closely distal to, the target lesion. Thus it appears that current DES regimes do not adequately service the needs of diabetic patients suffering from vascular diseases.
What is needed is a method of treating vascular disease in diabetics that addresses the risk of TLR and attendant MACE. This invention provides such a method.